Hyaluronic acid (HA) is used extensively in tissue engineering scaffolds due to its important structural and signaling roles in a variety of tissues, including the joint. It is a nonsulfated glysocaminoglycan (GAG) composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. The carboxylate group of glucuronic acid allows for relatively facile crosslinking and chemical modification of HA forming hydrogels or sponges, which has led to its evaluation as a scaffold material for a variety of tissues. However, the resultant HA-based scaffolds exhibit little similarity with the natural structure and presentation of HA found in the body. The bioactivity of HA is highly dependent on the molecular weight of the polymer and its associations with other proteins and extracellular matrix (ECM) components, and it is unclear how crosslinked HA scaffolds would affect cellular behavior compared to its natural presentation. Furthermore, the covalent modification of the HA backbone itself may significantly change its biological activity in unanticipated ways. A more natural, biologically relevant presentation of the HA may yield greater insight into the effects of HA-based scaffolds for tissue engineering, and may better potentiate tissue repair.
Cartilage tissue engineering aims to develop an effective therapy to repair articular cartilage lost due to trauma or disease. Cartilage has poor endogenous repair capacity, and currently available therapies are largely ineffective at producing a robust, healthy repair tissue. Given the aging population and increasing incidence of cartilage damage and osteoarthritis, there is significant interest in cartilage repair and restoring joint function. Biomaterials play an important role in serving as a scaffold to direct tissue repair. Tissue engineering scaffolds normally are composed of combinations of biological and synthetic polymer systems. While biological polymer systems often exhibit good bioactivity and regeneration potential, they frequently are mechanically weak, and difficult to control and purify. Attempts to chemically modify biological polymers to increase scaffold strength and control are often challenging and may cause a loss of biological activity. In contrast, synthetic systems boast a high degree of control over physical properties but exhibit little to no biological activity. Of recent interest is the combination of synthetic materials with biologically active molecules in order to form bio-synthetic composite materials that share the high degree of control found in synthetic materials with the biological functionalities found in biological polymers. These composite biomaterials include synthetic polymers modified with bioactive proteins or peptides to introduce specific biological functionalities such as cell adhesion, growth factor activity, or cell-mediated degradation.
Lubrication in tissues is also important to maintain a low-friction movement within a number of biological systems, including the pleural cavity, the surface of the eye, and diarthroidal joints. In diarthrodial joints, healthy painless movement is facilitated by both molecules at the tissue surface and in the lubricating synovial fluid. Synovial fluid bathes the joint surface with several molecules that contribute to boundary lubrication including lubricin, surface active phospholipids, and HA. The role of each of these components has been supported and challenged on the basis of various in vitro studies on cartilage lubrication, however in a healthy joint these molecules work together synergistically to reduce friction coefficients in boundary lubrication to achieve normal physiological performance. Today, therapeutic options to enhance tissue lubrication focus only on replacing or enhancing the lubricant in the fluid phase.
The breakdown of joint lubrication is a major hallmark of osteoarthritis (OA), stimulating significant interest in understanding and enhancing joint lubrication to improve overall joint health. Only ˜10% of the cartilage surface area comes into direct contact with the opposite surface during walking in the healthy knee, suggesting the role of boundary lubrication is relatively small. Osteoarthritic knees are further challenged by narrow intra-articular spaces, roughened cartilage surfaces, and often abnormal joint motion. All of these contribute to a much greater reliance on boundary lubrication at the same time that many boundary lubricants are depleted and disrupted by inflammatory processes. The resultant higher friction leads to pain, accelerated degeneration of cartilage, and disease progression. HA is believed to improve joint lubrication through its viscoelastic properties at high molecular weights, although biological functions may also play a role. As a result, one common clinical treatment for OA is injection of HA directly into the joint to improve synovial lubrication. Despite the physical and biological attributes of HA, clinical results of HA injections have been inconclusive and suspect due to the clearly observable rapid turnover of HA molecules within the joint after injection and limited ability to target areas where increased lubrication is needed.
The major limitation of HA implantation and use in lubrication in a joint or in cartilaginous tissues, however, is its longevity. For example, it has been shown that when injected into a joint, HA remains only for 24 hours.
Hence, the duration of an enhancement/repair/treatment achieved with hydrogel compositions is limited in time, and frequently requires the recipient to undergo additional and expensive repeat injections/treatments to maintain a desired effect. Hence, a need continues to exist in the tissue repair and reconstructive arts for improved HA containing biomaterial compositions which improve retention of HA in the hydrogel and are longer lasting.